Hereditary disorders, such as hemophilia and familial hypercholesterolemia, are representative of refractory diseases, many therapies for which only control worsening of patients' conditions using symptomatic treatments. For example, hemophilia is a hereditary disorder which results from mutations in genes coding for blood coagulation factors expressed in the liver, such as factor VIII or IX, and is treated with treatments administered from outside the body which compensate for these defect factors. However, patient's own immune responses may elicit circulating anti-coagulation factors, leading to discontinuing these treatments.
On the other hand, familial hypercholesterolemia (FH) is a hereditary disorder due to deficiency of the LDL (low-density lipoprotein) receptor expressed in the liver. In homozygotic patients, cholesterol-lowing drugs such as statins have no effects against the disorder. FH patients are required to reduce the value of cholesterol in the blood by periodic dialysis, which dialysis causes a great deal of physical and economic burdens and cannot inhibit the progression of arteriosclerosis.
As therapies for these disorders caused by decreased or lost functions of liver cells, liver transplantation or implantation of liver cells isolated from healthy individuals has been used, but these are not generally used yet, because of the problem of shortage of donors and heavy physical burdens on patients. On the other hand, remarkable developments in regenerative therapies using regenerative medicine, cell/tissue engineering, genetic engineering, and the like provide the path to conquer refractory diseases. As sources of cellular materials employed in these regenerative therapies, attention has been attracted to adult stem cells derived from mesenchymal tissues, in particular, somatic stem cells derived from adipose tissues which can be harvested with safety and ease and propagated in culture. However, in order to achieve the induction of differentiation of these stem cells to particular tissues or cells and their culturing outside the body, huge amounts of cost and labor are required, and thus there remain problems to be solved.
It has been reported by Seo et al. group that the implantation of adipose-derived mesenchymal stem cells in the liver resulted in their differentiation into hepatocytes (Non-Patent Document 1). Similar reports presume that from the fact that non-human stem cells derived from adipose tissues can engraft in the liver and are positive for albumin in immunohistological characterization, these stem cells have been differentiation-induced into hepatocytes in regional sites. However, it is unclear whether or not the hepatocytes reported to be differentiated and to engraft are active, and a problem arises that the number of engrafted cells is significantly small.